trypsinogen and Chronic-Disease

The past decade has witnessed remarkable progress in the genetics of chronic pancreatitis. Despite these accomplishments, the understanding of the molecular mechanisms through which PRSS1 and SPINK1 mutations cause chronic pancreatitis has remained sketchy. Pancreatitis-associated gene mutations are believed to result in uncontrolled trypsin activity in the pancreas. Experimental identification of the disease-relevant functional alterations caused by PRSS1 or SPINK1 mutations proved to be challenging, however, because results of biochemical analyses lent themselves to different interpretations. This article focuses on PRSS1 mutations and summarizes the salient biochemical findings in the context of the mechanistic models that explain the connection between mutations and hereditary pancreatitis.

Topics: Carrier Proteins; Chronic Disease; Genetic Variation; Humans; Pancreatitis; Point Mutation; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

The discovery of PRSS 1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. TheR122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.

Topics: Chronic Disease; Humans; Mutation; Pancreatitis; Risk Factors; Trypsin; Trypsinogen

There was some recent progress in the understanding of genetic risk factors in chronic pancreatitis. Due to this progress some of the traditional views of the subject will change. Today, genetic risk factors are attributed a much more important role that in the past. The frequency and strength of mutations were higher than expected. Strong variants were the rare autosomal-dominant mutations N29I and R122H of PRSS1 (cationic trypsinogen) and homozygous N34S of SPINK1 (pancreatic secretory trypsin inhibitor). Other mutations (heterozygous N34S, CFTR) were of lower relevance but still mediate a higher risk than alcohol consumption. The course of genetically determined pancreatitis is rather mild. In the long term pancreas cancer was found in some patients but apart from non-smoking no adequate prophylactic strategy is available up to now.

Topics: Carrier Proteins; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Disease Progression; Humans; Mutation; Pancreatic Neoplasms; Pancreatitis; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Abdominal Pain; Alcohol Drinking; Chronic Disease; Diabetes Mellitus; Fibrosis; Gallstones; Humans; Hypercalcemia; Hyperlipidemias; Malabsorption Syndromes; Mutation; Pancreas; Pancreatitis; Risk Factors; Smoking; Trypsin; Trypsinogen

Inflammatory disease of the pancreas falls into two major classifications: acute and chronic. Acute pancreatitis is a reversible process, whereas chronic pancreatitis produces irreversible changes in the architecture and function of the pancreas. The recent finding that mutations in the gene encoding cationic trypsinogen are associated with hereditary pancreatitis, the identification of genes that increase the risk for developing chronic pancreatitis, and advances in cell biology have contributed greatly to our understanding of the molecular mechanisms leading to pancreatitis. Although pancreatitis is less common in children than in adults, it still occurs with regularity and should be considered in any child with acute or chronic abdominal pain. The major difference between pancreatitis in children and adults lies in the etiologies and outcome of acute pancreatitis and in the etiology of chronic pancreatitis. The treatment of acute and chronic pancreatitis is similar at all ages.

Topics: Acute Disease; Animals; Carrier Proteins; Child; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Pancreatitis; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Acute Disease; Carrier Proteins; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Genetic Testing; Humans; Pancreatitis; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

The classical feature of hereditary pancreatitis (HP) is characterized by recurrent episodes of acute pancreatitis or a priori chronic pancreatitis in several members of one family. In 1996, the identification of the first HP-associated mutation in the cationic trypsinogen gene provided a breakthrough in our understanding of the pathogenesis of chronic pancreatitis. In the following years, several different mutations in the same gene have been found in a large number of investigated families. Most intriguing, HP patients have a more than 50-fold increased risk of pancreatic ductal cancer in comparison with expected pancreatic cancers in the general population. Variants of the major intrapancreatic trypsin antagonist SPINK1 have implications for more common forms of chronic pancreatitis. Research has focussed on the SPINK1-N34S-mutation, which is closely associated with tropical, alcoholic, or "idiopathic" chronic pancreatitis. Chronic pancreatitis represents a variable part of the cystic fibrosis syndrome, which is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Several groups have reported an increased prevalence of CFTR mutations in patients with chronic pancreatitis of different etiology. In this review, we summarize interesting clinical and biochemical features of genetic variants in these genes which are associated with chronic pancreatitis.

Topics: Carrier Proteins; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatic Neoplasms; Pancreatitis; Poland; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Adult; Chronic Disease; Disease Progression; Female; Humans; Male; Mutation; Pancreatitis; Pancreatitis, Alcoholic; Registries; Trypsin; Trypsinogen; Twins, Monozygotic

Chronic pancreatitis remains a challenging and frustrating clinical problem. In the past few years, however, advances in genetic and immunologic research have spawned new insights and approaches to chronic pancreatitis. Genetic and environmental risk assessment may help identify individuals who are likely to develop severe chronic pancreatitis early in the disease course, and allow targeted attention to reduce confounding risks and slow or prevent this problem in the future.

Topics: Chronic Disease; Humans; Models, Biological; Pancreatitis; Risk Factors; Trypsin Inhibitors; Trypsinogen

Hereditary pancreatitis (HP) is a disease which has been discovered quite recently. The inheritance is autosomally dominant with 80% penetrance. It gives the same symptoms as acute pancreatitis in early childhood and ends up with chronic pancreatitis. In 60% of the patients, a mutation in the trypsinogen gene can be demonstrated. The remaining 40% of the HP patients are diagnosed on the basis of clinical criteria. The acute and the chronic pancreatitis are treated as usual. It is important to recognize the disease because patients with HP have a 50 times increased risk of developing pancreatic cancer. At the age of 70, 40% have developed pancreatic cancer. This risk doubles for cigarette smokers. Screening programmes for HP in order to prevent pancreatic cancer are, however, expensive and troublesome.

Topics: Acute Disease; Adult; Aged; Child; Chronic Disease; Genetic Predisposition to Disease; Genetic Testing; Humans; Mutation; Pancreatic Neoplasms; Pancreatitis; Risk Factors; Trypsin; Trypsinogen

Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies have demonstrated that alcohol consumption alone does not directly cause pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present before the mechanisms protecting the pancreas from pancreatitis are circumvented and pancreatitis develops. The discovery that mutations in the cationic trypsinogen gene (R122H, N29I) predisposed to acute and chronic pancreatitis focused attention on possible genetic predispositions. Mutations in the cationic trypsinogen gene, however, are rarely associated with alcoholic chronic pancreatitis. Mutations in the SPINK1 gene (e.g. N34S) provide a threefold increased risk, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations continue to be investigated. However, the major cofactor associated with alcoholic chronic pancreatitis is yet to be identified.

Topics: Acute Disease; Alcohol Dehydrogenase; Alcohol Drinking; alpha 1-Antitrypsin; Animals; Carrier Proteins; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; HLA Antigens; Humans; Intercellular Signaling Peptides and Proteins; Mutation; Pancreatitis, Alcoholic; Polymorphism, Genetic; Risk Factors; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Genetic changes associated with some forms of chronic pancreatitis have been recently defined. There are three genes that play a role, each with a variety of genotypes and different pathologic mechanisms and clinical correlations. Selection of the appropriate diagnostic tests requires integration of the clinical and family history and the interpretation of results has a significant impact on genetic counseling for the patient and family. The relative significance of some variant alleles is still under investigation as they are common in the population and show low penetrance. Knowledge of the pathophysiology of each abnormal allele could lead the way towards more specific therapeutic options in the future.

Topics: Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Counseling; Genetic Testing; Humans; Molecular Diagnostic Techniques; Pancreas; Pancreatitis; Serine Proteinase Inhibitors; Trypsin; Trypsinogen

Pancreatitis has a proven genetic basis in a minority of patients.. Review of the literature on genetics of pancreatitis.. Ever since the discovery that in most patients with hereditary pancreatitis a mutation in the gene encoding for cationic trypsinogen (R122H) was found that results in a gain of trypsin function', many other mutations in the cationic trypsinogen gene, as well as in the gene encoding for pancreatic secretory trypsin inhibitor, have been found in patients with chronic pancreatitis. Furthermore, mutations in other genes, like the mucoviscoidosis-gene encoding for a chloride channel, and in genes encoding for enzymes involved in the metabolism of ethanol, have been linked to chronic pancreatitis. This article reviews the highlights that have been achieved in this field of pancreatic research.. Recent data suggest that genetics may play a role in the pathogenesis of pancreatitis.

Topics: Chronic Disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatitis; Trypsin; Trypsinogen

Topics: alpha 1-Antitrypsin; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Humans; Mutation; Pancreatitis; Risk Factors; Serine Proteinase Inhibitors; Trypsin; Trypsinogen

Topics: alpha 1-Antitrypsin; Child; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatitis; Prevalence; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Acute Disease; Animals; Antigens, Neoplasm; Biomarkers, Tumor; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Genetic Diseases, Inborn; Genetic Heterogeneity; Humans; Lectins, C-Type; Mice; Molecular Biology; Mutation; Pancreatitis; Pancreatitis-Associated Proteins; Proteins; Rats; Risk Factors; Trypsinogen

GENETIC RISK FACTORS: Recently, several genetic risk factors for chronic pancreatic diseases were found. In patients with chronic pancreatitis several mutations of the cationic trypsinogen were identified. In the majority of these subjects an autosomal dominant disease was observed. Mutations in the pancreatic secretory trypsin inhibitor (SPINK 1) were found in 20% of subjects with idiopathic, in 5% of those with alcoholic chronic and in 50% of those with tropical pancreatitis. Further variants were identified in CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), a chlorid transporter initially identified a disease-causing molecule in cystic fibrosis. In approximately 20-25% of the patients with chronic pancreatitis a mutation of one of these genes can be found.. A genetic investigation is useful when there is evidence for a family history of chronic pancreatitis and, at absence of typical risk factors, in patients with onset of disease earlier than 35-40 years of age.. In addition to alcohol abstinence the patients should be advised not to smoke. National and international registers as well as self-aid groups exist.

Topics: Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Genetic Predisposition to Disease; Humans; Pancreatitis; Pancreatitis, Alcoholic; Risk; Trypsin; Trypsinogen

Topics: alpha-Amylases; Chronic Disease; Genetic Predisposition to Disease; Humans; Mutation; Pancreatitis; Plant Proteins; Trypsin Inhibitors; Trypsinogen

In the last few years, several genes have been identified as being associated with hereditary and idiopathic chronic pancreatitis (CP), i.e. PRSS1, CFTR and SPINK1. In this study, we investigated 164 unrelated children and adolescents with CP for mutations in disease-associated genes by direct DNA sequencing, SSCP, RFLP and melting curve analysis. In 15 patients, we detected a PRSS1 mutation (8 with A16V, 5 with R122H, 2 with N29I), and in 34 patients, a SPINK1 mutation (30 with N34S, 4 with others). SPINK1 mutations were predominantly found in patients without a family history (29/121). Ten patients were homozygous for N34S, SPINK1 mutations were most common in 'idiopathic' CP, whereas patients with 'hereditary' CP predominantly showed a PRSS1 mutation (R122H, N29I). In patients without a family history, the most common PRSS1 mutation was A16V (7/121). In conclusion, our data suggest that CP may be inherited in a dominant, recessive or multigenetic manner as a result of mutations in the above-mentioned or as yet unidentified genes. This challenges the concept of idiopathic CP as a nongenetic disorder and the differentiation between hereditary and idiopathic CP. Therefore, we propose to classify CP as either 'primary CP' (with or without a family history) or 'secondary CP' caused by toxic, metabolic or other factors.

Topics: alpha 1-Antitrypsin; Child; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatitis; Serine Proteinase Inhibitors; Trypsin; Trypsinogen

Hereditary pancreatitis is an uncommon cause of chronic pancreatitis in Western society. It should be suspected when chronic pancreatitis presents in young adults. The diagnosis is made when chronic pancreatitis is present in several members of the same family who are determined not to have other risk factors for chronic pancreatitis. Molecular research focusing on mutations in the trypsinogen gene has uncovered the genetic defects associated with hereditary pancreatitis, and this knowledge has suggested the possible pathophysiologic mechanism of this disease. Because patients with hereditary pancreatitis develop their disease early in life they are very likely to require treatment for complications. As in patients with chronic pancreatitis of other etiologies those with hereditary pancreatitis should be treated medically for acute exacerbations. When complications occur or when the disease causes intractable pain surgery is recommended. Surgical therapy is tailored to the patient's pancreatic anatomy based on endoscopic retrograde cholangiopancreatography or CT scan. The two patients described in this report underwent successful longitudinal pancreaticojejunostomy (Puestow procedure) with good results. Finally it has been shown that patients with hereditary pancreatitis are at increased risk for developing pancreatic adenocarcinoma. Although not widely used pancreatic cancer screening programs have been suggested for surveillance of these patients.

Topics: Abdominal Pain; Adult; Chronic Disease; Female; Humans; Male; Mutation; Pancreaticojejunostomy; Pancreatitis; Risk Factors; Trypsinogen

Topics: Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatitis; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

For a long time the pathogenesis of pancreatitis has remained enigmatic. Recent developments in cellular and molecular biology, however, have provided a tremendous research impetus and some of its mysteries are finally being disclosed. This review discusses the implications of the discovery of the disease gene in hereditary pancreatitis and outlines recent advances in our understanding of the mechanism and site of trypsinogen activation and the role of immunocytes and cytokines in acute pancreatitis. With respect to chronic pancreatitis, this review focuses on its association with mutations in the cystic fibrosis conductance regulator gene and the mechanisms of pancreatic fibrosis. These advances in our knowledge of the pathogenesis of the disease, together with emerging biotechnological techniques, will boost the development of future therapies aimed at strategically targeting key pathophysiological processes involved in acute and chronic pancreatitis.

Topics: Acute Disease; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Humans; Mutation; Pancreatitis; Trypsinogen

The recent genetic discoveries in CP support the hypothesis that inappropriate intrapancreatic activation of zymogens by trypsin results in autodigestion and pancreatitis. Two different protective mechanisms prevent activation of the pancreatic digestive enzyme cascade. First, SPINK1 inhibits up to 20% of potential trypsin activity and, second, trypsin itself activates trypsin-like enzymes readily degrading trypsinogen and other zymogens. Pancreatitis may therefore be the result of an imbalance between proteases and their inhibitors within the pancreatic parenchyma. The discovery of PRSS1 mutations in families with CP was the first breakthrough in the understanding of the underlying genetic mechanisms. Enhanced trypsinogen activation may be the common initiating step in pancreatitis caused by these mutations. The discovery of SPINK1 mutations underlines the importance of the protease inhibitor system in the pathogenesis of CP. Thus, gain-of-function in the cationic trypsinogen resulting in an enhanced autoactivation, or loss-of-function mutations in SPINK1 leading to decreased inhibitory capacity, may similarly disturb the delicate intrapancreatic balance of proteases and their inhibitors. The recent findings of SPINK1, CFTR, and PRSS1 mutations in CP patients without a family history have challenged the concept of idiopathic CP as a non-genetic disorder and the differentiation between HP and ICP. There is a clear mode of autosomal dominant inheritance for some mutations (R122H, N291, possibly MIT), whereas the inheritance pattern (autosomal recessive, complex, or modifying) of other mutations (A16V, N34S) is controverted or unknown. The lack of mutations in the above-mentioned genes in many patients suggests that CP may also be caused by genetic alterations in yet unidentified genes. Evaluation of CP patients without an obvious predisposing factor, e.g. alcohol abuse, should include genetic testing even in the absence of a family history of pancreatitis. Finally, identification of further disease-causing genes will create a better understanding of pathogenesis and may help to develop specific preventive and therapeutic strategies.

Topics: Chronic Disease; Cystic Fibrosis; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Mutation; Pancreatitis; Polymorphism, Genetic; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Advances in molecular genetics have provided the powerful tools necessary to identify the key molecules and mechanisms that underly the disease process. Continued work in this area promises to reveal new insights as new disease genes are discovered. This article focuses on the insights into the cause of acute and chronic pancreatitis gained by investigation of the HP genes, the diagnosis of the known mutations, the fascinating observation of nonpenetrance, and a look at future directions.

Topics: Acute Disease; Amino Acid Sequence; Chronic Disease; Chymotrypsinogen; DNA Mutational Analysis; Genetic Predisposition to Disease; Genetic Testing; Humans; Molecular Sequence Data; Pancreatitis; Penetrance; Trypsinogen

Mutations of the cationic trypsinogen gene have been detected in hereditary pancreatitis. This article reviews current understanding of their function and clinical significance.. An unrestricted Medline search was conducted using the key words hereditary pancreatitis and 'cationic trypsinogen . Additional material was obtained from references cited in original papers and recently published abstracts of meetings.. Cationic trypsinogen mutations have been identified in most, but not all, families with hereditary pancreatitis. This confirms existing evidence that premature trypsinogen activation plays a central role in the pathogenesis of human pancreatitis. Patients currently clinically defined as having hereditary pancreatitis should be screened for the presence of cationic trypsinogen mutations. A subgroup of patients with non-hereditary pancreatitis may also benefit from being screened for these mutations. Patients with hereditary pancreatitis should be entered into prospective, multicentre trials investigating secondary screening for pancreatic cancer. Gene therapy for hereditary pancreatitis is beyond current technological capability but remains a future therapeutic prospect for this often debilitating condition.

Topics: Acute Disease; Cations; Chronic Disease; Humans; Mutation; Pancreatic Neoplasms; Pancreatitis; Risk Factors; Trypsinogen

Hereditary pancreatitis is an autosomal dominant form of chronic pancreatitis. It presents with recurrent attacks of acute pancreatitis, usually starting in early childhood. The attacks may vary from mild abdominal pain to pancreatic necrosis, splenic vein thrombosis, pseudocysts and death. Ultimately chronic pancreatitis ensues with unrelenting pain, calcifications, endocrine and exocrine dysfunction. The penetrance is estimated at 80%. With the use of genetic linkage analysis the gene for hereditary pancreatitis was placed on the long arm of chromosome 7 (7q35). Mutational analysis identified cationic trypsinogen as the disease gene. Cationic trypsinogen mutations are thought to result in resistance of this molecule to autolysis.

Topics: Adult; Child, Preschool; Chromosomes, Human, Pair 7; Chronic Disease; Diagnosis, Differential; Genetic Linkage; Genetic Predisposition to Disease; Humans; Mutation; Netherlands; Pancreatitis; Penetrance; Trypsin; Trypsinogen

Topics: Acute Disease; Chronic Disease; Humans; Mutation; Pancreatitis; Trypsinogen

Despite the recent development of medical imaging technology, chronic pancreatitis can only be diagnosed when the disease is fully established. This is due to the lack of specific and sensitive markers for this disease. The discovery of mutations in the cationic trypsinogen gene in patients with hereditary pancreatitis and a high incidence of mutations in the cystic fibrosis transmembrane conductance regulator gene in patients with chronic pancreatitis might be important clues to understanding the molecular mechanisms of this disease. The interaction between ethanol and ion channels might be the missing link between alcohol ingestion and chronic pancreatitis.

Topics: Adult; Aged; Alcoholism; Amino Acid Substitution; Animals; Biomarkers; Chloride Channels; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Dogs; Ethanol; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Models, Biological; Pancreatitis; Point Mutation; Protein Conformation; Trypsin; Trypsinogen

The recent discovery that mutations in the trypsinogen gene are responsible for acute and chronic pancreatitis, and that patients with hereditary pancreatitis are at great risk for pancreatic cancer, has opened the door to understanding many aspects of pancreatic disease. This review focuses on the clinical presentation of hereditary pancreatitis, the mechanism of disease, and implications of this disease on understanding acute and chronic pancreatitis.

Topics: Acute Disease; Amino Acid Substitution; Chronic Disease; Genetic Predisposition to Disease; Humans; Mutation, Missense; Pancreatic Neoplasms; Pancreatitis; Trypsinogen

Hereditary pancreatitis is an unusual form of acute and chronic pancreatitis with a familial predisposition. Recently, the gene mutations causing most cases of hereditary pancreatitis have been identified in the cationic trypsinogen gene. The known mutations are trypsinogen R117H and N211. These may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms used by the pancreas to eliminate prematurely activated trypsin. Accumulation of active trypsin mutants are hypothesized to initiate a digestive enzyme activation cascade in the pancreatic acinar cells leading to autodigestion, an intense inflammatory response, and acute pancreatitis. The observation that these patients also develop typical chronic pancreatitis and may later develop pancreatic cancer provides strong evidence that these conditions are linked. Knowledge of the pathophysiological conditions leading to acute and chronic pancreatitis and the development of a transgenic mouse expressing the mutant human trypsinogen genes will provide directions and tools necessary for the effective treatment or prevention of this human disease.

Topics: Animals; Chronic Disease; Disease Models, Animal; Genetic Diseases, Inborn; Humans; Mice; Pancreatic Neoplasms; Pancreatitis; Prognosis; Sensitivity and Specificity; Trypsinogen

Topics: Acute Disease; Chronic Disease; Computer Simulation; Humans; Models, Biological; Mutation; Pancreatitis; Trypsinogen

Topics: Acute Disease; Chronic Disease; Cytoplasmic Granules; Enzyme Activation; Enzyme Precursors; Humans; Lysosomes; Pancreatitis; Trypsinogen

Topics: Acute Disease; Alcoholism; Calcinosis; Cholecystitis; Chronic Disease; Enzyme Activation; Humans; Kinins; Lactoferrin; Pancreatitis; Protein Biosynthesis; Protein-Energy Malnutrition; Shock; Trypsin; Trypsinogen

To assess the relation between circulating cathodic trypsinogen (CT) levels and exocrine pancreatic function, and to compare the radioimmunological with the enzymatic measurement of duodenal trypsin, we evaluated exocrine pancreatic function in 34 controls and in 32 patients with proven chronic pancreatitis (CP). There was no relation between CT and the volume rate of pancreatic secretion, nor did serum CT levels correlate with the concentration output of duodenal bicarbonate in controls. However, in CP patients, there was a low value of the correlation coefficient. A good relationship between serum CT levels and duodenal trypsin secretion was detected when the trypsin content was expressed as the mean value of both concentration and output. The enzymatic estimation of duodenal trypsin was related closely to its radioimmunological measurement, but there was better correlation of serum CT to duodenal immunoreactive than to enzymatic trypsin. In patients with CP, low levels were observed in 29% of cases with serum CT estimation, in 75% with duodenal bicarbonate, and in 63% and 79% with enzymatic and immunoreactive trypsin outputs, respectively. We conclude that serum CT levels may reflect the functioning mass of pancreatic acinar cells and that in assessing pancreatic secretory capacity, the immunoreactive measurement of trypsin excretion is more sensitive than the enzymatic measurement and as accurate as bicarbonate output.

Topics: Bicarbonates; Chronic Disease; Clinical Enzyme Tests; Female; Humans; Male; Pancreas; Pancreatitis; Radioimmunoassay; Trypsin; Trypsinogen

Topics: Acute Disease; Animals; Chronic Disease; Mice; Pancreatitis, Chronic; Trypsin; Trypsinogen

Topics: Child; Chronic Disease; False Negative Reactions; Humans; Infant, Newborn; Lung Diseases; Neonatal Screening; Sweat; Trypsinogen

Topics: Chronic Disease; Humans; Mutation; Pancreatitis; Pancreatitis, Chronic; Trypsin; Trypsinogen

Topics: Chronic Disease; Humans; Mutation; Pancreatitis; Pancreatitis, Chronic; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Gene polymorphisms, including those recently described in the claudin2 gene, have been implicated in recurrent acute (RAP) and chronic pancreatitis (CP). In India, RAP and CP have been associated with SPINK1 polymorphism. In this study, we evaluated the association of claudin2 and PRSS1-PRSS2 polymorphisms with idiopathic RAP and CP.. We included 101 prospectively followed patients with documented idiopathic RAP (IRAP) and 96 patients who presented with idiopathic chronic pancreatitis (ICP) without previous history of AP. Controls were 156 unrelated individuals undergoing master health check or with non-specific symptoms. All the samples were genotyped for the SNPs rs7057398 in the claudin2 (CLDN2) gene and rs10273639 in the PRSS1 gene on Realtime polymerase chain reaction platform. Clinical data pertaining to patient and disease characteristics were recorded.. Claudin2 and PRSS1 polymorphisms were seen in a significantly higher proportion of female patients (P = 0.01 and 0.039, respectively). Thirty-three (32.7%) patients with IRAP developed features of early CP during follow-up (mean [95% confidence interval, CI] duration of 11.3 [8.9-13.7] months). Female patients with claudin2 (rs7057398) CC genotype were at significantly higher risk for IRAP (odds ratio [OR] [95% CI] 6.75 [1.82-23.67]; P = 0.004) and progression from IRAP to CP (OR [95% CI] 7.05 [1.51-33.01]; P = 0.007). CT genotype of PRSS1 (rs10273639) was associated IRAP (OR [95% CI] 2.59 [1.1-6.13]; P = 0.030), and both CT and CC genotypes with ICP in women (OR [95% CI] 2.86 [1.12-7.31]; P = 0.033 and 3.73 [1.03-13.59]; P = 0.048, respectively).. In this study, we have demonstrated the association of claudin2 (rs7057398) polymorphism with IRAP and progression of IRAP to CP, and PRSS1 (rs10273639) polymorphism with IRAP and ICP.

Topics: Acute Disease; Adolescent; Case-Control Studies; Child; Chronic Disease; Claudin-2; Disease Progression; Female; Follow-Up Studies; Genetic Association Studies; Humans; India; Male; Pancreatitis; Polymorphism, Single Nucleotide; Prospective Studies; Real-Time Polymerase Chain Reaction; Recurrence; Trypsin; Trypsinogen; Young Adult

Hereditary pancreatitis, an autosomal dominant disease with approximately 80% penetrance, can be caused by both 'gain-of-function' missense and copy number mutations in the cationic trypsinogen gene (PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/PRSS1 gene in a French white family with hereditary pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3-5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent 'double gain-of-function' effect, acting simultaneously as a 'quantitative' copy number mutation and a 'qualitative' missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.

Topics: Amino Acid Sequence; Amino Acid Substitution; Base Sequence; Chronic Disease; Female; Genetic Diseases, Inborn; Humans; Male; Molecular Sequence Data; Mutant Chimeric Proteins; Mutation, Missense; Pancreatitis; Pedigree; Trypsin; Trypsinogen

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Topics: Base Sequence; Chronic Disease; DNA Primers; Haplotypes; Humans; Hydrolysis; Models, Molecular; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Trypsin; Trypsinogen

Defects of PRSS1, SPINK1, CFTR and AAT are considered causative or predisposing to pancreatitis. The aim of this study was to evaluate the impact of these defects into molecular pathology of chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP).. Ninety-two children with CP or ARP, 55 family members and 50 controls were investigated. The subjects were screened for PRSS1 mutations: R122H, R122C, A16V, N29I; SPINK1 N34S variant; panel of 14 CFTR defects: INNOLiPA CFTR12, CFTRdele2,3 and IVS8-T variant or panel of 3 CFTR defects-F508del, CFTRdele2,3 and IVS8-T; AAT mutations: E264V, E342K.. We identified 1 mutated allele in at least 1 of 4 genes in 31 of 92 patients and 12 of 50 controls (P = 0.157). Mutations in SPINK1 and PRSS1 were most frequent. PRSS1 mutations were identified mainly in CP patients (9.6% of CP vs 2.5% of ARP alleles, P = 0.094), whereas N34S SPINK1 mutation was present with comparable frequency in CP and ARP patients (7.7% vs 10.0%, P = 0.768). The frequency of mutations in CFTR alleles was similar to controls (4.9% vs 5%, P = 0.587). Overall frequency of AAT mutations was lower than in the controls. Family studies showed that defects in the examined genes did not always segregate with disease.. PRSS1 defects seem to be causative for pancreatitis, whereas defects in SPINK1 are suggested to be associated with the disease. No association between CFTR mutations and pancreatitis was observed. The importance of AAT variants remains speculative.

Topics: Acute Disease; Adolescent; Adult; Alleles; alpha 1-Antitrypsin; Carrier Proteins; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Mutation; Pancreatitis; Recurrence; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/or endocrine impairment. It is well documented that mutations in the cationic trypsinogen (PRSS1) gene can cause hereditary pancreatitis. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and the serine protease inhibitor Kazal type 1 (SPINK1) genes are also associated with pancreatitis.. We analyzed 381 patients with a primary diagnosis of chronic or recurrent pancreatitis using the Ambry Test: Pancreatitis to obtain comprehensive genetic information for the CFTR, SPINK1, and PRSS1 genes.. The results identified 32% (122/381) of patients with 166 mutant CFTR alleles, including 12 novel CFTR variants: 4375-20 A>G, F575Y, K598E, L1260P, G194R, F834L, S573C, 2789 + 17 C>T, 621+83 A>G, T164S, 621+25 A>G, and 3500-19 G>A. Of 122 patients with CFTR mutations, 5.5% (21/381) also carried a SPINK1 mutation, and 1.8% (7/381) carried a PRSS1 mutation. In addition, 8.9% (34/381) of all patients had 1 of 11 different SPINK1 mutations. Another 6.3% (24/381) of the patients had 1 of 8 different PRSS1 mutations. Moreover, 1.3% of the patients (5/381) had 1 PRSS1 and 1 SPINK1 mutation. A total 49% (185/381) of the patients carried one or more mutations.. Comprehensive testing of the CFTR, PRSS1, and SPINK1 genes identified genetic variants in nearly half of all subjects considered by their physicians as candidates for genetic testing. Comprehensive test identified numerous novel variants that would not be identified by standard clinical screening panels.

Topics: Acute Disease; Adolescent; Adult; Aged; Carrier Proteins; Child; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genetic Variation; Humans; Infant; Male; Mutation; Pancreatitis; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

The identification of a specific mutation in the human cationic trypsinogen gene in large kindreds with hereditary pancreatitis was the key to understand the genetic background of chronic pancreatitis. Rapidly, other variants within the same gene were identified-even in small families with a minority of patients. Later, mutations of the most important intrapancreatic trypsin inhibitor SPINK1 were found with high prevalence in patients with idiopathic, tropical and alcoholic chronic pancreatitis. We summarize interesting genetic and biochemical findings, point to clinical features and review recommendations for genetic analysis, follow-up and cancer prevention.

Topics: Carrier Proteins; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Genetic Predisposition to Disease; Genotype; Humans; Pancreas; Pancreatitis; Phenotype; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Proteinase-activated receptor 2 (PAR(2)), a G-protein-coupled receptor activated by serine proteinases such as trypsin, has been suggested to play an important role in inflammatory and fibroproliferative processes. In preterm infants, the development of bronchopulmonary dysplasia (BPD) is characterized by early pulmonary inflammation and subsequent interstitial fibrosis. High pulmonary trypsin-2 has been shown to be associated with the development of BPD. We studied the expression and distribution of PAR(2) and trypsin-2 by immunohistochemistry in autopsy lung specimens of fetuses (n = 10), of preterm infants who died of acute or prolonged respiratory distress syndrome (RDS) (n = 8 and n = 7, respectively) or BPD (n = 6), and of newborn infants without lung disease (n = 5) who served as controls. In prolonged RDS and BPD, PAR(2) immunoreactivity was significantly higher in bronchial epithelium when compared with infants without pulmonary pathology (p < 0.05 and p < 0.005, respectively). In alveolar epithelium, expression of PAR(2) was elevated in prolonged RDS when compared with newborn infants without pulmonary pathology (p < 0.05). Moreover, strong expression of PAR(2) was detected in myofibroblasts of thickened and fibrotic alveolar walls in prolonged RDS or BPD. Trypsin-2 was co-localized with PAR(2) in bronchoalveolar epithelium. These findings suggest that PAR(2), possibly activated by trypsin-2, may participate in inflammation and fibroproliferation associated with progression of RDS toward BPD in preterm infants.

Topics: Acute Disease; Bronchopulmonary Dysplasia; Case-Control Studies; Chronic Disease; Fetus; Humans; Immunohistochemistry; Infant, Newborn; Infant, Premature; Pulmonary Alveoli; Receptor, PAR-2; Respiratory Distress Syndrome, Newborn; Trypsin; Trypsinogen

Chronic pancreatitis: Only recently mutations in several genes were found in patients with chronic pancreatitis. In those with a familial chronic pancreatitis mutations of the cationic trypsinogen were identified and the variants N29I and R122H lead to an autosomal dominant disease. In this group of patients the mutation N34S of the trypsin inhibitor SPINK1 was detected. In so-called idiopathic pancreatitis both variants of the SPINK1 and of the CFTR (cystic fibrosis transmembrane conductance regular) were identified. Alterations in both genes were also found in patients with alcoholic chronic pancreatitis. The strongest risk factor for chronic pancreatitis were trypsinogen mutations N29I and R122H mutations. However, both SPINK1 and CFTR increased the risk for chronic pancreatitis to a higher level than alcohol consumption. A genetic investigation should be performed in familial disease and younger age, but also in patients without family history and higher age a mutation could be found. Pancreas cancer: In 10% of the patients with pancreas cancer other members of the family were affected from the disease. Some of them belong to well characterized familial syndroms like HNPCC or Peutz-Jeghers-syndrom. In a minority of the others a genetic factor may be found, too. In sporadic disease the development of the tumor is characterized by continued acquirement of genetic alterations described by the PanIN model (pancreatic intraepithelial neoplesia). This means that the evolution of the neoplasia progresses from normal tissue via epithelial hyperplasy (PanIN 1A), papillary hyperplasy without (PanIN 1B) and with dysplasy (PanIN 2) and carcinoma in situ (PanIN 3) to invasive pancreas cancer. The progression is associated with genetic alterations of the cells (mutations of ki-ras, p16, p53 etc.). This results in deterioration of control of the cell cycle and the apoptosis and explains the malignancy of the disease. These findings may be used in the future to develop newer therapeutic principles in order to improve the dismal prognosis of this disease.

Topics: Carrier Proteins; Cell Transformation, Neoplastic; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Susceptibility; DNA Mutational Analysis; Genes, Dominant; Genotype; Humans; Pancreatic Neoplasms; Pancreatitis; Pancreatitis, Alcoholic; Risk Factors; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Adult; Chronic Disease; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation; Pancreatitis; Pedigree; Trypsinogen

The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis-associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild-type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. Furthermore, in contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N29I had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis.

Topics: Adult; Aged; Carrier Proteins; Catalysis; Cathepsins; Chronic Disease; DNA Mutational Analysis; Enzyme Activation; Female; Humans; Intercellular Signaling Peptides and Proteins; Isoenzymes; Kinetics; Male; Middle Aged; Mutation; Pancreatitis; Pedigree; RNA, Messenger; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Mutation of Cationic trypsinogen gene is clearly associated with hereditary pancreatitis and plays an important role in the pathogenesis of pancreatitis. According to literature, this mutation is occasionally occurred in patients with pancreatitis in Western countries and Japan. The aim of this study was to find out whether the mutation was observed in Korean patients with chronic idiopathic pancreatitis.. Peripheral blood samples of 11 patients with chronic idiopathic pancreatitis were collected consecutively, and DNA was extracted from the samples. Polymerase chain reaction was performed in exon 2 and 3 of cationic trypsinogen gene. Then, DNA products were purified and sequenced.. The mutation was not found in exon 2 and 3 of cationic trypsinogen gene in these patients.. There was no cationic trypsinogen mutation in Korean patients with chronic idiopathic pancreatitis. Further large sampled cohort study is needed.

Topics: Adolescent; Adult; Chronic Disease; Female; Humans; Male; Middle Aged; Mutation; Pancreatitis; Polymerase Chain Reaction; Trypsin; Trypsinogen

Mutations in the cationic trypsinogen (protease, serine, 1 (trypsin 1); PRSS1) gene are causally associated with recurrent acute and chronic pancreatitis. We investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, Kazal type I; SPINK1) mutations, the role of SPINK1 mutations in these patients was also analysed.. The coding regions of PRSS1 and SPINK1 genes were sequenced in 290 controls and 198 patients, of whom 120 were diagnosed as idiopathic (ICP), 41 as alcoholic (ACP), and 37 as hereditary pancreatitis (HP). Twenty four unaffected relatives of HP probands were also analysed and genotype-phenotype correlations and statistical analyses were performed.. No mutations in the PRSS1 gene were detected in any of the patients, including HP patients, while the N34S mutation was observed in the SPINK1 gene in the majority of HP patients (73%). Similarly, 26.8% of ACP (11 of 41) and 32.5% (39 of 120) of ICP patients also had SPINK1 mutations. The N34S mutation was observed in both homozygous and heterozygous conditions. In comparison, only 2.76% of the control population had the N34S allele (p<0.001). The P55S mutation was observed in one ICP and one ACP patient, and in three normal individuals. Genotype-phenotype correlations did not suggest any significant difference in the age of onset, severity of disease, or pancreatic endocrine insufficiency in patients with or without mutated SPINK1 and irrespective of the allelic status of N34S SPINK1.. Irrespective of the aetiology, mutations in the PRSS1 gene are not associated with chronic pancreatitis, including HP. In contrast, the N34S mutation in the SPINK1 gene shows a significant correlation in these patients. A comparable phenotype in terms of age of onset, diabetes mellitus, and other phenotypic features in patients with or without SPINK1 mutations and N34S homozygotes and heterozygotes suggests that there may still be involvement of other genetic or environmental factors.

Topics: Adult; Chronic Disease; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Mutation; Pancreatitis; Pedigree; Phenotype; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Specific mutations in the cationic trypsinogen gene ( PRSS1) are disease-causing in patients with hereditary pancreatitis, but the genetic background still remains mysterious in about 40% of patients with the disease. It has been suggested that oxidative stress contributes to pancreatic damage. The glutathione s-transferases (GSTs) represent major detoxification enzymes that protect cells from oxidative stress.. In the present study we tested whether mutations in the MGST1 and GSTM3 genes or common deletions in the GSTT1 and GSTM1 genes are associated with hereditary pancreatitis. We analyzed the entire coding region of MGST1 and GSTM3 in 30 patients that were tested negative for PRSS1 mutations, and we studied 55 controls. For GSTT1 and GSTM1, we investigated 75 hereditary pancreatitis patients who had been tested negative for PRSS1 mutations, 135 hereditary pancreatitis patients with a PRSS1 mutation, and 183 controls. Patients were further subclassified with regard to age of onset of disease as a marker of severity.. No mutation was found in the MGST1 gene. In the GSTM3 gene, we detected a homozygous 670G > A polymorphism (V224I) with similar frequencies in patients and controls. We found no difference in the frequencies of the GSTT1 and GSTM1 null genotypes between patients and controls, and we detected no differences in age of onset in patients with or without GSTT1 and GSTM1 deletions.. We conclude that genetic alterations in the MGST1, GSTM3, GSTT1, and GSTM1 genes do not play a dominant role in hereditary pancreatitis.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Chronic Disease; DNA Mutational Analysis; Exons; Female; Gene Frequency; Genetic Predisposition to Disease; Glutathione Transferase; Homozygote; Humans; Infant; Male; Middle Aged; Open Reading Frames; Oxidative Stress; Pancreatitis; Polymerase Chain Reaction; Polymorphism, Genetic; Prognosis; Reference Values; Trypsin; Trypsinogen

Topics: Chronic Disease; Humans; Mutation; Pancreatitis; Trypsinogen

Topics: Chronic Disease; Humans; Mutation; Pancreatitis; Trypsin; Trypsinogen

Topics: Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Pancreatitis; Trypsin; Trypsinogen

Though hereditary pancreatitis is a very rare form of pancreatitis, the discovery of the gene for hereditary pancreatitis provides important implications for pancreatitis in general. A premature activation of trypsinogen is likely to occur not infrequently in our daily life as the onset of the disease is well advanced before a drinking habit starts. It probably goes unnoticed in normal individuals because normal inhibitory mechanisms described above prevent the development of pancreatitis. Any disorders or agents that cause abnormalities in this natural protective mechanism can cause pancreatitis. Genotype-phenotype analyses of CFTR mutations in chronic pancreatitis are necessary to establish the relationship between CFTR and this disease. It remains to be shown how a reduction of functional CFTR causes chronic pancreatitis.

Topics: Acute Disease; Chronic Disease; Cystic Fibrosis; Humans; Pancreatitis; Trypsinogen

Several genetic factors have been well known to predispose one to chronic pancreatitis (CP). However, little is known about the genetic factors that may provide a protective effect against the disease. Having found a nonsense mutation (c.111C>A; Y37X) and a splicing mutation (IVS2+1G>A) in the cationic trypsinogen gene (protease, serine, 1; PRSS1) in alcoholics without the development of CP, but not in alcoholics with CP and patients with hereditary or idiopathic CP, we propose that while "gain of function" mutations in the PRSS1 gene predispose one to pancreatitis, "loss of function" mutations in the gene may protect one against the disease.

Topics: Adult; Aged; Alcoholism; Chronic Disease; Exons; Female; Genotype; Humans; Male; Middle Aged; Mutation; Pancreatitis; Trypsin; Trypsinogen

The clinical course of chronic pancreatitis in patients with mutations of cationic trypsinogen and the trypsin inhibitor SPINK1 has not yet been characterized.. Cationic trypsinogen (PRSS1) and the serine protease inhibitor, Kazal type 1 (SPINK1), were analyzed in patients with pancreatitis of unclear origin.. Eighty subjects with trypsinogen mutations (21x N29I, 59x R122H) and 59 patients with the SPINK1 N34S variant (11 homozygous, 48 heterozygous) were included in the study.. In patients with mutations of PRSS1 (N29I, R122H) and SPINK1 (N34S) the parameters such as calcification, dilatation of the main pancreatic duct, diabetes mellitus, hospital treatments, and surgery were recorded.. Case control studies were performed to compare both mutational groups, and the follow-up time served as a matching criterion. The Kaplan-Meier analysis was used to estimate the time course of the symptoms.. Ten years after the onset of the disease, the probability (+/-SE) of symptoms in patients with PRSS1 mutations was as follows: 1st hospital stay: 86+/-4%; calcification: 21+/-4%; duct dilatation: 26+/-9%; surgery: 19+/-5%; diabetes: 6+/-5%. After 25 years, we found the following data: 1st hospital stay: 96+/-3%; calcification: 38+/-8%; duct dilatation: 38+/-8%; surgery: 37+/-10%; diabetes: 28+/-8%. A case-control-study of 38 pairs of patients with either PRSS1 or SPINK1 mutations showed that the probability of duct dilatation, diabetes and calcification was slightly higher in patients having a SPINK1 mutation. There was no difference between those subjects with a homozygous or heterozygous SPINK1 mutation. In comparison to alcoholic chronic pancreatitis patients, the PRSS1 associated disease revealed a lower frequency of calcification and diabetes.. The progression of chronic pancreatitis was slightly more rapid in patients with SPINK1 mutations than in patients with cationic trypsinogen mutations, but was much less than in those having alcoholic chronic pancreatitis.

Topics: Case-Control Studies; Child; Chronic Disease; Disease Progression; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Mutation; Pancreatitis; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Mutations in cystic fibrosis transmembrane conductance regulator (CFTR), in cationic trypsinogen (PRSS1) and in serine protease inhibitor Kazal type 1 (SPINK1) genes have been associated with chronic pancreatitis (alcohol related, idiopathic and hereditary). However, the inheritance pattern is still not clear.. Eighty-two unrelated Brazilian patients with chronic pancreatitis (alcohol-related disease in 64, idiopathic disease in 16, and hereditary disease in 2). Two hundred unrelated individuals with an ethnic distribution comparable to the patients were studied as controls.. Detection of mutations in CFTR, PRSS1, and SPINK1 genes.. Mutations in the CFTR gene were found in 8 patients (9.8%) with chronic pancreatitis, 5 of them with idiopathic disease. Interestingly, the only clinical symptom in a male patient in the alcoholic group, who was a compound heterozygote (DeltaF508/R170C) for two CFTR mutations, was pancreatitis without infertility or pulmonary involvement. In the PRSS1 gene, the E79K change in exon 3 was found in one patient (1.2%) with alcohol-related chronic pancreatitis. Four different alterations were identified in the SPINK1 gene.. Mutations in the CFTR gene represent the major cause of idiopathic chronic pancreatitis in Brazilian patients. No mutation was found in the PRSS1 gene among our patients suggesting further genetic heterogeneity for hereditary and idiopathic chronic pancreatitis. Interestingly, the most frequent SPINK1 N34S mutation was not present in patients or controls. Moreover, the -253C allele for the SPINK1 gene was significantly more frequent in patients than controls (P=0.004), suggesting that it might represent a risk factor for the development of pancreatitis in our population.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brazil; Child; Chronic Disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Male; Middle Aged; Mutation; Pancreatitis; Pancreatitis, Alcoholic; Serine Proteinase Inhibitors; Trypsin; Trypsinogen

Recent genetic investigations into cationic trypsinogen and pancreatic secretory trypsin inhibitor (PSTI) led to the conclusion that mutations in either gene can contribute to the development of (hereditary) chronic pancreatitis. Since genetic animal models are not available yet, we have studied the Wistar-Bonn/Kobori (WBN/Kob) rat, a model for chronic pancreatitis (CP). To explore the possibility that PSTI may be secreted at lower levels or contain a mutation in the WBN/Kob rat, we investigated the masses of PSTI-I and -II and asked whether the ratio of PSTI/trypsinogen is decreased in animals with CP.. We collected pancreatic juice from WBN/Kob and Wistar rats aged 6-36 weeks and measured PSTI-I (ELISA) and trypsin.. PSTI-I and -II were identified in Wistar and WBN/Kob rats by mass spectrometry and N-terminal sequencing. Using a newly developed PSTI-I ELISA, we can show that the PSTI-I/trypsinogen ratio is not decreased but rather increased in WBN/Kob rats compared to healthy Wistar rats. No evidence for a PSTI mutation was found.. Our data does not support the hypothesis that a dysbalance of PSTI/trypsinogen ratio is a causative factor for CP.

Topics: Animals; Chronic Disease; Disease Models, Animal; Male; Pancreatitis; Protein Isoforms; Rats; Rats, Wistar; Reference Values; RNA, Messenger; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Acute Disease; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Pancreatic Neoplasms; Pancreatitis; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Adolescent; Chronic Disease; Female; Humans; Mutation; Pancreatitis; Trypsin; Trypsinogen

Tropical calcific pancreatitis (TCP) is a chronic pancreatitis unique to developing countries in tropical regions. The cause of TCP is obscure. Whereas environmental factors, such as protein energy malnutrition and ingestion of cassava, have been implicated, a genetic predisposition to the disease also may be important. In the present study we report on mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) gene in north Indian patients with TCP.. We studied 66 unrelated TCP patients (44 men, 49 with diabetes, and 6 with family history of TCP), 25 relatives, and 92 healthy control subjects. Samples were analyzed for SPINK1 variants (-53C>T, L14P, N34S, P55S, and 272T>C) and cationic trypsinogen (PRSS1) variants (A16V, K23R, N29I, and R122H) by melting curve analysis.. Twenty-nine patients (44%) carried the N34S missense mutation, of whom 9 (14%) were homozygotes. In contrast, only 2 (2.2%) control subjects were N34S heterozygotes (prevalence ratio 20.2; 95% confidence interval 5.0-81.8; P < 0.0001 vs. TCP). The severity of pancreatitis did not differ between TCP patients with or without N34S, or among those heterozygous or homozygous for N34S. Among TCP patients with or without diabetes, the frequency of N34S carriers (43% vs. 47%) and N34S homozygotes (14% vs. 12%) was similar.. TCP is highly associated with the SPINK1 N34S mutation. The high prevalence of N34S in TCP patients with and without diabetes suggests that these 2 subtypes have a similar genetic predisposition. The genetic predisposition to TCP resembles, at least in part, the idiopathic chronic pancreatitis found in industrialized countries.

Topics: Adult; Chronic Disease; Diabetes Mellitus; Family Health; Female; Heterozygote; Homozygote; Humans; India; Male; Pancreatitis; Pedigree; Point Mutation; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Adolescent; Adult; Age of Onset; Child; Chronic Disease; Humans; Mutation; Pancreatitis; Trypsin; Trypsinogen

Hereditary pancreatitis (HP) is usually caused by mutations in the cationic trypsinogen (PRSS1) gene, especially R122H or N29I. We sequenced the PRSS1 gene in the proband of families without these common mutations. Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion. The R122C mutation eliminates the arginine autolysis site as with R122H mutations. The N29T mutation may also enhance intrapancreatic trypsin activity as has been demonstrated in vitro. Identification of these new mutations requires special attention as commonly used detection methods may fail.

Topics: Adult; Amino Acid Substitution; Chronic Disease; Female; Humans; Male; Mutation; Pancreatitis; Pedigree; Phenotype; Polymorphism, Restriction Fragment Length; Trypsinogen

Mutations of the cationic trypsinogen (CT) and the serine protease inhibitor, Kazal type 1 (SPINK 1) are associated with chronic pancreatitis. After mutational screening of a cohort of patients with nonalcoholic chronic pancreatitis, we report three novel variants of the trypsinogen molecule and the clinical characteristics of the carriers.. The coding region of the exon 2 and 3 of the CT gene of 523 patients with chronic nonalcoholic pancreatitis (108 patients with suspected hereditary pancreatitis (HP) and 415 patients with "idio pathic" pancreatitis [IP]) and 82 controls was analyzed after polymerase chain reaction amplification. Clinical characteristics were obtained by questioning the patients and their relatives and physicians. HP was suspected when two members of a family had chronic pancreatitis. A restriction digestion was used to analyze the N34S mutation SPINK1.. The mutation R122H of the cationic trypsinogen was found in 21 index patients, N291 in six index patients, and A16V and D22G in one index patient, all from HP families. The N34S mutation of SPINK1 was found in two index patients with a family history of HP. In three patients, the novel point mutations L104P, R116C, and C139F of the cationic trypsinogen were found. A clear autosomally dominant inheritance of chronic pancreatitis was not present in these families. In 75 index patients from HP families (69.4%), no mutation could be found. The SPINK 1-mutation N34S was detected in only one patient carrying a CT mutation, and was found in 68 (16.4%) of patients with IP.. The R122H and N291 mutations of CT are the most common disease-associated mutations in HP; the N34S mutation of SPINK I is the most frequent genetic risk factor associated with IP. The CT gene carries several variations that could be associated with chronic pancreatitis. To avoid overestimating the pathogenetic impact of novel trypsinogen variants, a detailed clinical characterization of all patients with early onset chronic pancreatitis is mandatory.

Topics: Adult; Base Sequence; Chronic Disease; Cohort Studies; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Nuclear Proteins; Pancreatitis; Pedigree; Polymerase Chain Reaction; Sensitivity and Specificity; Trypsin; Trypsinogen

Mutations of the pancreatic serine protease inhibitor, Kazal type 1 (SPINK1), the cationic trypsinogen (PRSS1) and the cystic fibrosis transmembrane conductance regulator (CFTR) were reported to be genetic risk factors of chronic pancreatitis (CP). The aim of this study was to determine the role of genetic variants of the main serum antiproteinases alpha-1-antitrypsin (AAT) and alpha-2-macroglobulin (A2M) for the course of chronic pancreatitis.. 124 patients with non-alcoholic chronic pancreatitis (with PRSS1 or SPINK1 mutations or idiopathic pancreatitis) and 64 healthy controls were investigated for the AAT mutations PiS and PiZ, and the PiM determining variants R101H, V213A, E376D. In 101 subjects, the 'bait region' of A2M was sequenced. A pentanucleotide deletion in the bait region of A2M was analysed in 147 chronic pancreatitis (CP) patients and 87 controls.. The lowest prevalences of V213A and E376D were found in PRSS1 patients, whereas an increased rate of these mutations was present in the SPINK1 group, and the highest prevalence was found in patients with idiopathic pancreatitis. The prevalence of PiM variants was higher in patients with early onset CP than in late onset (P < 0.05 for E376D). The coding region of the bait region of A2M was of wild type in all investigated subjects. The A2M pentanucleotide deletion showed a homogenous distribution in patients and controls.. Our study suggests a moderating, but not predominant, role of AAT variants in the course of chronic non-alcoholic pancreatitis.

Topics: Adolescent; Adult; Aged; alpha 1-Antitrypsin; alpha-Macroglobulins; Base Sequence; Case-Control Studies; Chi-Square Distribution; Child; Child, Preschool; Chronic Disease; Cohort Studies; DNA Mutational Analysis; Female; Genetic Markers; Genetic Testing; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Pancreatitis; Polymerase Chain Reaction; Probability; Prognosis; Sensitivity and Specificity; Serine Proteinase Inhibitors; Severity of Illness Index; Trypsin; Trypsinogen

In the last 5 years, mutations in three genes, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the pancreatic secretory trypsin inhibitor (PSTI) gene, have been found to be associated with chronic pancreatitis (CP). In this study, using established mutation screening methods, we systematically analysed the entire coding sequences and all exon/intron junctions of the three genes in 39 patients with idiopathic CP (ICP), with a view to evaluating the relative contribution of each gene to the aetiology of the disease. Our results demonstrate that, firstly, 'gain-of-function' mutations in the PRSS1 gene may occasionally be found in an obvious ICP subject. Secondly, presumably 'loss-of-function' mutations in the PSTI gene appear to be frequent, with a detection rate of at least 10% in ICP and, finally, abnormal CFTR alleles are common: at least 20% of patients carried one of the most common CFTR mutations, and about 10% of patients were compound heterozygotes, having at least one 'mild' allele. Thus, in total, about 30% of ICP patients carried at least one abnormal allele in one of the three genes, and this is the most conservative estimate. Moreover, a trans-heterozygous state with sequence variations in the PSTI/CFTR genes was found in three patients. However, an association between the 5T allele in intron 8 of the CFTR gene and ICP remains unproven.

Topics: Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Female; France; Genetic Predisposition to Disease; Humans; Male; Mutation; Pancreatitis; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Although chronic pancreatitis is associated with risk factors such as alcoholism, hyperparathyroidism, and hypertriglyceridaemia, little is known of the actual aetiology of the disease. It is thought that inappropriate activation of trypsinogen causes pancreatitis, and indeed in cases of hereditary pancreatitis mutations of cationic trypsinogen (PRSS1) have been described. As serine protease inhibitor Kazal type 1 (SPINK1) is a potent natural inhibitor of pancreatic trypsin activity, we hypothesised that SPINK1 mutations would be more common than expected among an unselected cohort of adult chronic pancreatitis patients.. To detect the prevalence of SPINK1 mutations in a cohort of chronic pancreatitis patients.. DNA was isolated from a cohort of 115 adult patients with chronic pancreatitis of alcoholic (n=72), hereditary (n=10), idiopathic (n=24), and miscellaneous (n=9) origin. We performed mutational analysis for two PRSS1 mutations (R122H, N29I) and four specific SPINK1 gene mutations (M1T, L14P, N34S, P55S) and compared the results with a control group of 120 healthy Dutch subjects.. In six of the 10 patients that fulfilled the criteria for hereditary pancreatitis, but in none of the control subjects, mutations in the PRSS1 gene were found. In 14 patients we detected a SPINK1 mutation. Eleven patients were heterozygous for the N34S mutation and sequencing confirmed the homozygous state of N34S in a brother and sister. Two patients carried the P55S mutation, one as a compound heterozygote with N34S. The M1T and L14P SPINK1 mutations were not found in our cohort. The N34S mutation was detected in only two of 120 controls, while the P55S, M1T, and L14P mutations were absent in the same group. Patients with the N34S allele had a later onset of disease than those with PRSS1 gene mutations but earlier onset compared with the mutation negative group.. Identification of SPINK1 mutations in 12.2% of patients with adult alcoholic and idiopathic chronic pancreatitis suggests an important role for SPINK1 as a predisposing factor in adult chronic pancreatitis.

Topics: Adult; Aged; Base Sequence; Chronic Disease; Cohort Studies; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Pancreatitis; Pancreatitis, Alcoholic; Phenotype; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Topics: Adult; Base Sequence; Calcinosis; Chronic Disease; Diabetes Complications; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation; Pancreatitis; Phenotype; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Three-point mutations (R117H, N211, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies.

Topics: Acute Disease; Adult; Child; Chronic Disease; DNA Mutational Analysis; DNA Primers; Female; Humans; Male; Middle Aged; Mutation; Pancreatitis; Pedigree; Polymerase Chain Reaction; Recurrence; Trypsin; Trypsinogen

Several missense mutations, including R122H, N29I, K23R, A16V and D22G, in the cationic trypsinogen gene (PRSS1), have been associated with certain forms of hereditary pancreatitis (HP). Their occurrence in the idiopathic chronic pancreatitis (ICP) and whether novel mutations could be identified in PRSS1 remain to be further evaluated. These were addressed by the mutational screening of the entire coding sequence and the intronic/exonic boundaries of the PRSS1 gene in 221 ICP subjects, using a previously established denaturing gradient gel electrophoresis technique. Among the known PRSS1 mutations, only the R122H was detected in a single subject and the A16V in two subjects in the cohort, strengthening that HP-associated PRSS1 mutations are rare in ICP. Additional missense mutations, including P36R, E79K, G83E, K92N and V123M, were identified once separately. By analogy with the known PRSS1 mutations, predisposition to pancreatitis by some of them, particularly the V123M autolysis cleavage site mutation, is suspected. Functional analysis is expected to clarify their possible medical consequences.

Topics: Amino Acid Sequence; Chronic Disease; Cohort Studies; DNA Mutational Analysis; Humans; Molecular Sequence Data; Mutation; Mutation, Missense; Pancreatitis; Trypsin; Trypsinogen

Authors report two cases of childhood chronic pancreatitis, causing severe symptoms and common bile duct stenosis with cholestasis. Both patients had to be operated on. Chronic pancreatitis with calcification led to significant common bile duct stenosis in a 13 years old girl. After ERCP a double bypass procedure was performed (Wirsungo-jejunostomy and hepatico-jejunostomy). During 42 months follow-up the patient remained pain- and symptom-free gaining 16 kilograms. In a 9 years old girl severe stenosis of the intrapancreatic common bile duct and a small duct type chronic pancreatitis with extensive fibrosis was found. Treatment was Roux-en-Y hepatico-jejunostomy. Thirty-four months after the operation she is symptom-free with normal enzyme parameters. Authors report results of genetic investigations performed on registered chronic pancreatitis children and their families in Hungary, including the two operated cases. Two of the 5 patients were hereditary type, despite negative family history. Cationic trypsinogen gene R122H (R117H) mutation were detected in both patients. Chronic non-hereditary pancreatitis is a very rare disease in childhood but may cause severe secondary conditions requiring surgery.

Topics: Adolescent; Biliary Tract Surgical Procedures; Child; Cholestasis; Chronic Disease; Common Bile Duct; Constriction, Pathologic; Female; Fibrosis; Humans; Hungary; Male; Mutation; Pancreatitis; Trypsinogen

Hereditary, chronic pancreatitis is an autosomal dominant genetic disorder, frequently associated with two point mutations in the cationic trypsinogen gene. The mutations result in characteristic changes in the amino-acid sequence of trypsinogen: an arginine residue at position 117 is changed to histidine (Arg117-->His) or an asparagine residue at position 21 is replaced by isoleucine (Asn21-->Ile). Current opinion on the pathogenesis of hereditary pancreatitis suggests that the mutations lead to increased trypsin activity in the pancreatic tissue as a result of enhanced autoactivation of trypsinogen or decreased autocatalytic degradation (autolysis) of trypsin. To investigate the relationship between the altered properties of mutant trypsinogens and the pathomechanism of pancreatitis, wild-type and two mutant forms of recombinant human cationic trypsinogen were produced and autoactivation of trypsinogens and autolysis of trypsins were studied. The results indicate that trypsin stabilization (i.e. decreased autolysis) caused by the Arg117-->His mutation may contribute to the development of pancreatitis, however, the Asn21-->Ile mutation has no such effect. In contrast, enhanced autoactivation of mutant trypsinogens may contribute to the pathogenesis of both forms of hereditary pancreatitis. This notion is strongly supported by the clear correlation between the autoactivation rates of mutant trypsinogens and the severity of clinical symptoms.

Topics: Arginine; Asparagine; Chronic Disease; Enzyme Induction; Histidine; Humans; Isoleucine; Mutation; Pancreatitis; Trypsinogen

Mutations in the cationic trypsinogen gene have been detected in patients with hereditary pancreatitis (HP). This study investigates the prevalence of the R122H, N29I, A16V and -28delTCC mutations in the common, non-hereditary forms of chronic pancreatitis and in a HP family.. DNA was prepared from blood samples of 53 patients with chronic pancreatitis (36 alcoholic, 14 idiopathic and 3 hereditary), 20 alcoholic controls and 20 healthy, ethnically matched controls. The R122H and A16V mutations were identified by the polymerase chain reaction (PCR) and restriction enzyme digestion. A nested-PCR was used to identify the N29I mutation. The -28delTCC deletion and the C133807T polymorphism were sought by direct sequencing.. The R122H mutation was detected in 1 patient with alcoholic chronic pancreatitis and all 3 affected members of a HP family. The N29I, A16V and -28delTCC mutations were not detected in any of the study subjects. At the C133807T polymorphism, the C allele and C/C genotype were significantly increased in alcoholic chronic pancreatitis (p = 0.001 and p = 0.0004, respectively) while the T allele and CT genotype were significantly reduced (p = 0.001 and p = 0.004, respectively) compared to healthy controls.. Mutations of the cationic trypsinogen gene are rarely found in chronic pancreatitis patients of typical aetiology. Screening for these mutations should be considered in those with a family history consistent with hereditary pancreatitis but may also be appropriate in a well-defined subgroup of patients with non-hereditary chronic pancreatitis, i.e. those who have developed the disease before the age of 30.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; DNA; Female; Humans; Male; Middle Aged; Mutation; Pancreatitis; Polymerase Chain Reaction; Trypsin; Trypsinogen

Summary. The understanding of the pathogenesis of chronic pancreatitis is limited. Several theories (i. e. obstruction hypothesis) were suggested in the past but could not be confirmed by experimental data. As a formal description of the course of the disease, the necrosis-fibrosis concept seems to be very attractive. According to this theory, there is no significant difference in the pathogenesis of acute and chronic pancreatitis. A major step was the identification of mutations of the cationic trypsinogen, the secretory trypsin inhibitor (SPINK 1) and the cystic-fibrosis protein (CFTR) in some patients. Investigation of these mutations may significantly contribute to a better understanding of the pathogenesis of chronic pancreatitis.

Topics: Adult; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Fibrosis; Humans; Mutation; Necrosis; Pancreas; Pancreatic Neoplasms; Pancreatitis; Risk Factors; Trypsin Inhibitors; Trypsinogen

We determined the clinical manifestations of hereditary pancreatitis in nearly 30 families.. The two trypsinogen mutations N29I and R122H were identified in a group of 550 patients with chronic pancreatitis of unclear origin. The following criteria were used to characterize the severity of chronic pancreatitis (one point each): calcifications, cysts, dilation of the pancreatic duct, diabetes, hospital treatment, and operation. Stages were defined as stage 0 (no points), stage 1 (one to two points), stage 2 (three to four points), and stage 3 (more than four points). Smoking and drinking habits were also recorded.. Six families with the N29I mutation (25 subjects with the mutation) and 21 families with the R122H mutation (76 subjects with the mutation) were identified. The median ages for the onset of disease were 11 years in N29I and 10 years in R122H patients. The severity of chronic pancreatitis and symptoms were similar for both mutations. About 26% (n = 26) of the 101 subjects carrying a mutation were asymptomatic, and 42% (n = 42) had mild disease (stage 1). Twenty-nine percent (n = 29) had moderate disease (stage 2), and only 4% (n = 4) had severe disease (stage 3).. Symptoms of patients with the N29I or R122H trypsinogen mutation were generally similar. The majority of subjects with trypsinogen mutations had mild disease or was asymptomatic.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Chronic Disease; Health Behavior; Humans; Middle Aged; Mutation; Pancreas; Pancreatitis; Polymerase Chain Reaction; Severity of Illness Index; Trypsin; Trypsinogen

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC-->CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.

Topics: Adult; Arginine; Chronic Disease; Cysteine; Exons; Germany; Humans; Male; Pancreatitis; Point Mutation; Polymerase Chain Reaction; Recurrence; Sequence Analysis, DNA; Trypsinogen; Turkey

We report a 25-year-old male with hemosuccus pancreaticus associated with hereditary pancreatitis. He was originally diagnosed as having familial chronic pancreatitis at the age of 12, because his brother was also diagnosed as having pancreatitis. No history of pancreatitis was found in their parents. The patient was admitted because of a growing pancreatic pseudocyst. While he had undergone conservative treatment for the pseudocyst, computed tomography incidentally revealed a pancreatic pseudoaneurysm. Endoscopic examination revealed spontaneous bleeding from the major papilla. Interventional embolization was successfully performed. An R122H mutation in the cationic trypsinogen gene was identified in this patient, his brother, and his mother, indicating that they have hereditary pancreatitis. To our knowledge, this is the first report of hemosuccus pancreaticus associated with hereditary pancreatitis. Mutational screening is useful for the diagnosis of hereditary pancreatitis, especially in patients whose diagnosis is inconclusive based on the traditional clinical criteria.

Topics: Adult; Amino Acid Substitution; Aneurysm, False; Chronic Disease; Exons; Female; Humans; Male; Mutation, Missense; Pancreas; Pancreatitis; Pedigree; Tomography, X-Ray Computed; Trypsinogen

Hereditary pancreatitis has been shown to be caused by one of two mutations (R117H and N21I) of the cationic trypsinogen gene (PRSS1). Families with hereditary pancreatitis in the north of England were investigated for these mutations. The clinical features associated with each mutation were compared.. In individuals from nine families with hereditary pancreatitis, DNA was screened for the R117H and N21I mutations. All five exons of the cationic trypsinogen gene were also sequenced to search for additional mutations. Haplotype analysis was carried out to identify common ancestors. Clinical data were collected.. The R117H mutation was identified in three families and N21I in a further five. The R117H mutation was associated with a more severe phenotype than N21I in terms of mean(s.d.) age of onset of symptoms (8.4(7.2) versus 16. 5(7.1) years; P = 0.007) and requirement for surgical intervention (eight of 12 versus four of 17 patients respectively; P = 0.029). Haplotype analysis suggested that each mutation had arisen more than once.. Two mutations in the cationic trypsinogen gene cause hereditary pancreatitis in eight of nine families originating in this region. The R117H mutation is associated with a more severe form of the disease in terms of age at onset of symptoms and requirement for surgical intervention.

Topics: Age of Onset; Chronic Disease; DNA; Female; Haplotypes; Humans; Male; Mutation; Pancreatitis; Pedigree; Polymerase Chain Reaction; Trypsinogen

Historically, trypsinogens/trypsins have been one of the most extensively studied enzyme models of protein structure and function. They have received renewed attention after the identification of mutations in the cationic trypsinogen gene as being associated with hereditary pancreatitis. A survey of the literature revealed five cloned cDNAs, but only three protein products of human trypsinogens, and their nomenclature has been confusing. The availability of the complete genomic sequencing of the human trypsinogen gene family made it possible to provide a systematic review of the genes, cDNAs, and protein products of human trypsinogens and to clarify some controversial issues. Further, the confusing coexistence of two systems for naming the cationic trypsinogen mutations is addressed.

Topics: Alternative Splicing; Amino Acid Sequence; Amino Acid Substitution; Chromosomes, Human, Pair 7; Chronic Disease; Cloning, Molecular; DNA, Complementary; Exons; Humans; Isoenzymes; Molecular Sequence Data; Multigene Family; Mutation; Pancreatic Juice; Pancreatitis; Pseudogenes; Sequence Alignment; Sequence Homology, Amino Acid; Trypsinogen

To evaluate serum feline trypsin-like immunoreactivity (fTLI) concentration and results of abdominal ultrasonography, CBC, and serum biochemical analyses for diagnosis of pancreatitis in cats.. Prospective study.. 28 cats with clinical signs compatible with pancreatitis.. Serum fTLI concentrations were determined, and abdominal ultrasonography, CBC, and serum biochemical analyses were performed prior to histologic evaluation of pancreatic, hepatic, and intestinal specimens. On the basis of histologic results, cats were categorized as having a normal pancreas (n = 10), pancreatic fibrosis with ongoing inflammation (9), pancreatic fibrosis without inflammation (4), and acute necrotizing pancreatitis (5). Serum fTLI concentrations and results of CBC, serum biochemical analyses, and histologic evaluation of hepatic and intestinal specimens were compared among groups.. Significant differences in serum fTLI concentrations or any hematologic or biochemical variable were not detected among the 4 groups of cats. Median serum fTLI concentrations were 51 micrograms/L (range, 18 to 200 micrograms/L) in cats with a normal pancreas, 32 micrograms/L (range, 12 to > 200 micrograms/L) in cats with pancreatic fibrosis and ongoing inflammation, 124 micrograms/L (range, 36 to > 200 micrograms/L) in cats with pancreatic fibrosis without ongoing inflammation, and 30 micrograms/L (range, 24 to 84 micrograms/L) in cats with acute necrotizing pancreatitis. We detected a high prevalence of concurrent hepatic and intestinal tract disease in cats with pancreatitis.. In cats with clinical signs of pancreatitis, serum fTLI concentration is poorly associated with histopathologic diagnosis.

Topics: Acute Disease; Animals; Cat Diseases; Cats; Chronic Disease; Female; Male; Pancreas; Pancreatitis; Radioimmunoassay; Trypsin; Trypsinogen

Mutations of the cationic trypsinogen have been described in hereditary pancreatitis. We report a new trypsinogen mutation in the activation peptide of the proenzyme in a family with chronic pancreatitis.. The coding region of the cationic trypsinogen gene was sequenced after polymerase chain reaction amplification. The following peptides homologous to the N-terminal end of cationic trypsinogen were synthesized (one-letter code, mutated amino acid underlined): wild-type peptide, APFDDDDKIVGG; pD22G, APFDDDGKIVGG; pK23R, APFDDDDRIVGG. The sequences of pD22G and pK23R correspond to the recently identified mutation K23R and to the mutation described here (D22G). To mimic trypsinogen activation, these peptides were digested with trypsin for 30 minutes at pH 5.0-8. 0, and the fragments were analyzed by high-performance liquid chromatography.. In a family with clinical evidence of hereditary chronic pancreatitis, a missense mutation of codon 22 (GAC-->GGC) of the cationic trypsinogen was found. This mutation results in a substitution of aspartic acid by glycine; therefore, the mutation was called D22G. Chromatographic analysis of tryptic digests of the peptides pD22G and pK23R showed hydrolysis rates of 22% and 75%, respectively, whereas the wild-type peptide was hydrolyzed at only 6%. The cleavage rates were reduced at lower pH, and no hydrolysis occurred without trypsin.. The activation peptides of the trypsinogen variants D22G and K23R could be released at a higher rate than in wild-type trypsinogen, resulting in increased amounts of trypsin in the pancreas, which could initiate pancreatitis.

Topics: Adult; Cations; Chronic Disease; DNA Mutational Analysis; Enzyme Activation; Family Health; Female; Gene Expression; Humans; Hydrogen-Ion Concentration; Male; Mutation, Missense; Oligopeptides; Pancreatitis; Pedigree; Trypsin; Trypsinogen

To establish whether serum pancreatic enzyme determination is useful in the identification of patients with chronic pancreatitis and in revealing the presence of exocrine pancreatic insufficiency. A total of 50 patients with chronic pancreatitis were included in the investigation: 19 were studied during a painful attack of the disease and 31 were observed during clinical remission of the disease and underwent a secretin-caerulein test; 21 of the 31 patients had severe pancreatic insufficiency. Thirty patients with non-pancreatic digestive diseases were also studied. Serum amylase, pancreatic isoamylase, lipase, trypsinogen and elastase- were determined in all patients.. Serum levels of the 5 enzymes studied were significantly higher in patients with pancreatic pain than in those studied during a clinical remission of the disease, and in those with non-pancreatic digestive diseases. In patients with chronic pancreatitis studied during clinical remission of the disease serum levels of pancreatic isoamylase and trypsinogen were significantly lower than in those patients with non-pancreatic digestive diseases. Considering only low serum concentrations of the five enzymes studied in diagnosing chronic pancreatitis, trypsinogen showed a sensitivity of 28%, specificity of 100%, a predictive value of a positive test of 100% and a predictive value of a negative test of 96.4%. In the 21 patients with severe pancreatic insufficiency, abnormally low serum concentrations of trypsinogen were found in 12 patients (57%), of lipase and elastase-1 in 6 (29%), of pancreatic isoamylase in 5 (24%), and of amylase in 3 (14%).. Serum pancreatic enzymes can not be considered a useful tool to identify patients with pancreatic insufficiency. However, of the five enzymes studied, serum trypsinogen appears to be a useful marker in the diagnostic work-up of chronic pancreatitis.

Topics: Adult; Aged; Aged, 80 and over; Amylases; Biomarkers; Chronic Disease; Female; Humans; Isoamylase; Lipase; Male; Middle Aged; Pancreatic Elastase; Pancreatitis; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Trypsinogen

We studied the role of the increase in the calcium concentration in pure pancreatic juice of alcoholic noncalcified chronic pancreatitis. Pure pancreatic juice was obtained endoscopically. The pancreatic juice from patients with chronic pancreatitis was adjusted to pH 7.5; then the calcium concentration was adjusted to 0.4, 2.9, 5.4, or 10.4 mmol/L. Artificial precipitates were produced by incubation of the samples at 37 degrees C for 6 hours. Proteins in the artificial precipitates were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the protein patterns were compared with the patterns of natural protein plugs from patients with chronic pancreatitis. The amount of the precipitate increased as the added calcium increased. The protein patterns of SDS-PAGE of the artificial precipitates were similar to those of protein plugs. Albumin, a-amylase, lipase, trypsinogen, and chymotrypsinogen were identified by immunoblotting both in the precipitate and in the protein plug. The increased calcium concentrations in pancreatic juice induced the formation of precipitates whose protein composition was similar to that of protein plugs. An increased calcium concentration in human pancreatic juice may play an important role in the pathogenesis of protein plugs.

Topics: Adult; Aged; Albumins; alpha-Amylases; Calcium; Chemical Precipitation; Chronic Disease; Chymotrypsinogen; Electrophoresis, Polyacrylamide Gel; Humans; Hydrogen-Ion Concentration; Immunoblotting; Lipase; Male; Middle Aged; Pancreatic Juice; Pancreatitis, Alcoholic; Proteins; Trypsinogen

Topics: Amino Acid Substitution; Base Sequence; Chronic Disease; DNA; DNA Mutational Analysis; Genotype; Molecular Sequence Data; Mutation; Pancreatitis; Sequence Homology, Nucleic Acid; Trypsin; Trypsinogen

We recently experienced a rare case of chronic pancreatitis in a 13-year-old Japanese boy. Recently, in hereditary pancreatitis patients, some mutations have been identified in the trypsinogen gene. The purpose of this study was to investigate whether the same mutations could also be found in this patient. Polymerase chain reaction (PCR)-amplified products of his cationic and anionic trypsinogen genes were examined by direct sequence analysis. The gene analysis failed to show any mutation in any exons and their flanking intronic sequences of his trypsinogen genes. These findings indicate that the chronic calcifying pancreatitis in the present patient is "idiopathic", and thus a rare case of juvenile pancreatitis.

Topics: Adolescent; Calcinosis; Chronic Disease; DNA Mutational Analysis; Humans; Japan; Male; Mutation; Pancreatitis; Trypsinogen

Topics: Acute Disease; Chronic Disease; Humans; Mutation; Pancreatitis; Trypsinogen

Single-point mutations in the cationic trypsinogen gene have been reported in hereditary pancreatitis kindreds in the white population. The aim of the present study was to investigate whether similar gene mutations are present in Japanese hereditary pancreatitis kindreds.. All five exons of the cationic trypsinogen gene were amplified by polymerase chain reaction and sequenced in six Japanese families with hereditary pancreatitis.. Two types of single-point mutation in the cationic trypsinogen gene, which were identical with those reported in white families with hereditary pancreatitis, were observed in separate Japanese families with hereditary pancreatitis: 21Asn (AAC) to Ile (ATC) (N21I) in exon 2 and 117Arg (CGC) to His (CAC) (R117H) in exon 3. Pancreatitis occurred at more advanced ages in patients with the N21I mutation than in those with the R117H mutation. Besides normal polymorphisms in exons 4 and 5, no mutation was found in patients in the remaining four families with hereditary pancreatitis, 21 patients with sporadic chronic pancreatitis, or five normal subjects.. These results show heterogeneity, but no racial specificity, in the cationic trypsinogen gene mutations in hereditary pancreatitis kindreds. A distinctive clinical feature for each of the mutation types is suggested: adult onset for the N21I mutation and childhood onset for the R117H mutation.

Topics: Adolescent; Adult; Age of Onset; Amino Acid Sequence; Child; Child, Preschool; Chronic Disease; Exons; Female; Humans; Japan; Male; Molecular Sequence Data; Pancreatitis; Pedigree; Point Mutation; Polymerase Chain Reaction; Sequence Analysis, DNA; Trypsinogen

Hereditary pancreatitis is a rare form of chronic recurrent pancreatitis. A family, in which 11 members had chronic pancreatitis, five had diabetes, and two had pancreatic cancer, was studied, and hereditary pancreatitis was diagnosed in all patients by demonstrating the mutation in exon 3 of the cationic trypsinogen gene (R117H). The clinical implications of genotypic analysis in hereditary pancreatitis are discussed.

Topics: Adolescent; Chronic Disease; Female; Humans; Mutation; Pancreatitis; Pedigree; Trypsinogen

In pancreatitis, a key role has been attributed to the inappropriate conversion of trypsinogen to trypsin. Recently, two mutations of the cationic trypsinogen gene were found in families with hereditary pancreatitis. This study was conducted to determine the spectrum and frequency of cationic trypsinogen mutations in unrelated patients with idiopathic or hereditary chronic pancreatitis (CP).. DNA samples from 44 unrelated children and adolescents with CP (30 patients with idiopathic CP and 14 with hereditary CP) and from 56 family members were investigated. The cationic trypsinogen gene was screened for mutations by single-strand conformation polymorphism analysis and DNA sequencing.. A mutation in the cationic trypsinogen gene was detected in 5 patients: in 2 patients with a family history of CP and in 3 patients with idiopathic CP. In 1 patient the formerly described R122H mutation was detected. In 4 patients a hitherto unknown mutation was found at the signal peptide cleavage site leading to an alanine to valine exchange in codon 16. The mutations were inherited in all cases. In 95 unrelated control individuals the A16V mutation was not found.. Heterozygosity for the A16V mutation is strongly associated with CP. These results indicate that a significant percentage of patients with idiopathic CP may have a genetic basis for their disorder; therefore, genetic testing should be included in the diagnostic evaluation of these patients.

Topics: Adolescent; Amino Acid Sequence; Cations; Child; Child, Preschool; Chronic Disease; Female; Humans; Infant; Male; Molecular Sequence Data; Mutation; Pancreatitis; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Protein Sorting Signals; Trypsinogen

Nine out of 48 (19%) patients referred to a pancreatic clinic with a presumed diagnosis of idiopathic chronic pancreatitis have been shown to have mutations in the cationic trypsinogen gene (PRSSI), consistent with a previously unsuspected diagnosis of hereditary pancreatitis.

Topics: Adult; Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Chronic Disease; Diagnosis, Differential; DNA Mutational Analysis; Humans; Pancreatitis; Pancreatitis, Alcoholic; Polymerase Chain Reaction; Risk Factors; Trypsinogen

Topics: Child; Chronic Disease; Humans; Molecular Biology; Mutation; Pancreatitis; Trypsinogen

Topics: Alanine; Amino Acid Substitution; Chronic Disease; Humans; Mutation; Pancreatitis; Trypsinogen; Valine

Topics: Alanine; Amino Acid Sequence; Amino Acid Substitution; Biological Transport; Chronic Disease; Genetic Testing; Humans; Molecular Sequence Data; Mutation; Pancreatitis; Protein Sorting Signals; Sequence Homology, Amino Acid; Trypsinogen; Valine

Topics: Chronic Disease; Humans; Mutation; Pancreatitis; Trypsinogen

A 71-year-old woman was admitted with the suspected diagnosis of pancreatic carcinoma. As a child she had had repeated attacks of abdominal pain of undetermined cause. When aged 48 years she had developed diabetes mellitus. Her now 42-year-old daughter had from the age of 9 years suffered from repeated attacks of acute pancreatitis that had finally led to chronic pancreatitis. The patient's 15-year-old grandchild was having recurrent bouts of abdominal pain.. Imaging procedures revealed calcifications in the pancreas and an infiltrating space-occupying lesion, about 3 cm in diameter, in the head of the pancreas with lymph node and liver metastases. Cytological analysis of material aspirated from the space-occupying mass showed typical findings of ductal pancreatic carcinoma. FURTHER TESTS, TREATMENT AND COURSE: At first the patient's course was not typical for a genetically-determined disease, but the family history raised the suspicion of hereditary pancreatitis. A genetic test (Afl-III-RFLP test) demonstrated the mutation Arg 117 His in the cationic trypsinogen gene in all diseased or symptomatic family members. The patient died of the complications of the pancreatic cancer.. Genetic tests are valuable in the diagnosis of hereditary pancreatitis, because the increased cancer risk can be met by frequent examinations in affected family members.

Topics: Abdominal Pain; Acute Disease; Adolescent; Adult; Aged; Calcinosis; Chronic Disease; Family; Fatal Outcome; Female; Humans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Point Mutation; Polymorphism, Restriction Fragment Length; Recurrence; Risk Factors; Tomography, X-Ray Computed; Trypsinogen; Ultrasonography

Hereditary pancreatitis is an autosomal dominant disorder with incomplete penetrance. It is characterised by recurring episodes of severe abdominal pain and often presents in childhood. Recently, a mutation in the cationic trypsinogen gene was identified in this disease. Previously, only one mutation at residue 117 of the trypsinogen gene has been found in the five separate hereditary pancreatitis families, four from the USA and one from Italy. Alteration of the Arg117 site is believed to disrupt a fail-safe mechanism for the inactivation of trypsin, leading to autodigestion of the pancreas under certain conditions. Molecular analysis of the trypsinogen gene was carried out on a hereditary pancreatitis family from the UK. The same G to A mutation at residue 117 was identified in this family, suggesting that this is a common mutation in hereditary pancreatitis.

Topics: Chronic Disease; Female; Humans; Male; Mutation; Pancreatitis; Pedigree; Polymerase Chain Reaction; Recurrence; Trypsinogen

Topics: Acute Disease; Animals; Chronic Disease; Dogs; Humans; Pancreas; Pancreatitis; Point Mutation; Trypsin; Trypsinogen

The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Although environmental factors may play a role in its pathogenesis, a specific genetic predisposition may be necessary. The genetic mutation responsible for hereditary pancreatitis was described recently. Unlike in patients with hereditary pancreatitis, we found a lack of the R117H mutation in the cationic trypsinogen gene in all patients with tropical pancreatitis from Bangladesh.

Topics: Adolescent; Adult; Bangladesh; Chronic Disease; DNA; Female; Humans; Male; Pancreatitis; Point Mutation; Tropical Climate; Trypsinogen

Topics: Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Chromosomes, Human, Pair 7; Chronic Disease; Genes, Dominant; Genetic Markers; Humans; Pancreatitis; Trypsinogen

We recently identified a single R117H mutation in the cationic trypsinogen gene in several kindreds with an inherited form of acute and chronic pancreatitis (HP1), providing strong evidence that trypsin plays a central role in premature zymogen activation and pancreatitis. However, not all families studied have this mutation. The aim of this study was to determine the disease-causing mutation in kindreds with hereditary pancreatitis that lack the previously identified mutation.. Clinical features of the HP1 kindreds were compared with those of the new kindreds (HP2), and genetic linkage analysis, screening for mutations through DNA sequencing, and screening an unaffected population were performed.. The onset of symptoms was delayed and hospitalizations were fewer in HP2 compared with HP1 (P < 0.05). Linkage of the disease gene to chromosome 7q35 was established (logarithm of the odds, 3.73). Mutational screening identified a single A to T mutation resulting in an asparagine to isoleucine transition mutation at position 21 (N21I) in cationic trypsinogen. The mutation was absent in 94 unrelated individuals, representing 188 unique chromosomes.. The identification of a second mutation in the cationic trypsinogen gene (HP2) suggests a dominant role of trypsin in premature protease activation-mediated forms of acute pancreatitis. The pathogenesis of hereditary pancreatitis also suggests that chronic pancreatitis may result from recurrent acute pancreatitis.

Topics: Acute Disease; Adenine; Asparagine; Chromosome Mapping; Chromosomes, Human, Pair 7; Chronic Disease; Female; Genetic Linkage; Hospitalization; Humans; Isoleucine; Male; Pancreatitis; Pedigree; Point Mutation; Recurrence; Thymine; Trypsinogen

Protein analysis of intraductal precipitates and calculi is important to elucidate the mechanism of stone formation in chronic pancreatitis. We revealed human cationic trypsin immunoreactivity in protein extracts of pancreatic stones from 11 of 13 patients with chronic calcified pancreatitis, ranging from 0 to 42.3 ng/micrograms protein. On gel filtration the immunoreactivity eluted as one peak, which is identical to that of human cationic trypsinogen. On immunostaining of pancreatic stone, using an immunogold technic and scanning electron microscopy, the immunoreactivity was observed more densely in the amorphous portion of the center of the stones than in the concentric laminar layer of the periphery. Only negligible activity was detected for elastase 1 or amylase in the stone extracts. These results suggest that the presence of trypsinogen in pancreatic stone is not due to coprecipitation or adsorption of pancreatic enzymes but that trypsinogen is more likely involved in an initial step of intraductal precipitate formation than in a subsequent step of stone formation. However, the absence of trypsinogen in the stones from two of the 13 patients also suggests that trypsinogen is not the sole protein initiating precipitate formation.

Topics: Adult; Aged; Calculi; Chronic Disease; Female; Humans; Immunohistochemistry; Male; Microscopy, Electron, Scanning; Middle Aged; Pancreatic Diseases; Pancreatitis; Proteins; Trypsin; Trypsinogen

Investigations of pancreatic juice revealed new insights into the pathogenesis of chronic pancreatitis (cP). But many results are contradictory. In this paper pure human pancreatic juice from patients with cP (n = 14) was compared with results obtained from normal subjects (n = 22). The pancreatic juice was obtained endoscopically recording the absorption (280 nm) simultaneously. By means of this special technique 4 fractions could be exactly distinguished: 1. wash-out-period, 2. phase of secretin action, 3. phase of pancreozymin (CCK) action, and 4. post-CCK-phase. Total protein, trypsinogen, zinc sodium, and potassium were determined. In fraction 1 (wash-out-period) mean values of protein, trypsinogen and zinc are lower in patients with cP compared with control subjects. In case of zinc the difference is statistically significant. In fraction 2 (secretin-phase) no differences could be detected between cP and control subjects. In contrast in fraction 3 (CCK-phase) mean values of protein and trypsinogen are lower in control subjects than in patients with cP. But the standard deviations are so high that all differences are not statistically significant. The results indicate that under fasting conditions the pancreatic juice content of protein, trypsinogen and zinc is lower in patients with cP. But patients with cP can be stimulated much better with CCK than control subjects. Till now such a different behaviour during wash-out-period and CCK-stimulation is not reported in the literature.

Topics: Cholangiopancreatography, Endoscopic Retrograde; Cholecystokinin; Chronic Disease; Humans; Pancreatic Function Tests; Pancreatic Juice; Pancreatitis; Potassium; Proteins; Secretin; Sodium; Trypsinogen; Zinc

The serum behavior of amylase, pancreatic isoamylase, lipase, trypsinogen, and elastase 1 was studied in 145 patients with pancreatic disease and in 66 patients with abdominal pain of nonpancreatic origin, for the purpose of evaluating the relative diagnostic utility of their assays. In 34 patients with acute pancreatitis, serum lipase, trypsinogen, and elastase 1 were elevated in all 34, pancreatic isoamylase in 33 (97%) and amylase in 30 (88%). Ten of these acute pancreatitis patients were followed sequentially for seven days: the variations in their serum enzyme levels were parallel, although the lipase, trypsinogen, and particularly the elastase 1 elevations persisted longer than did those of amylase and pancreatic isoamylase. Among the patients with chronic pancreatitis, either in painful relapse (N = 19) or with pancreatic cysts (N = 15), the respective percentages of enzymes elevations were: 79 and 80% for elastase 1, 68 and 67% for trypsinogen, 63 and 73% for pancreatic isoamylase, 58 and 60% for lipase, 53 and 60% for amylase. In the 52 chronic pancreatitis patients studied during clinical remission, serum enzyme behavior varied greatly, and a majority of the assays (60%) were normal; even in the case of severe pancreatic exocrine insufficiency, normal as well as abnormally high and low enzyme values were seen. Highly variable enzyme behavior was also seen in the 40 patients with pancreatic cancer, and elastase I was the most frequently (35%) elevated enzyme in this group as well. Among the patients with abdominal pain of nonpancreatic origin, abnormally high enzyme levels were present in percentages ranging from 6% for lipase to 21% for trypsinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adult; Aged; Amylases; Chronic Disease; Clinical Enzyme Tests; Female; Humans; Isoamylase; Lipase; Male; Middle Aged; Pancreatic Diseases; Pancreatic Elastase; Pancreatic Neoplasms; Trypsinogen

The pancreatic stone protein and its secretory form (PSP-S) are inhibitors of CaCO3 crystal growth, possibly involved in the stabilization of pancreatic juice. We have established the structure of PSP-S mRNA and monitored its expression in chronic calcifying pancreatitis (CCP). A cDNA encoding pre-PSP-S has been cloned from a human pancreatic cDNA library. Its nucleotide sequence revealed that it comprised all but the 5' end of PSP-S mRNA, which was obtained by sequencing the first exon of the PSP-S gene. The complete mRNA sequence is 775 nucleotides long, including 5'- and 3'- noncoding regions of 80 and 197 nucleotides, respectively, attached to a poly(A) tail of approximately 125 nucleotides. It encodes a preprotein of 166 amino acids, including a prepeptide of 22 amino acids. No overall sequence homology was found between PSP-S and other pancreatic proteins. Some homology with several serine proteases was observed in the COOH-terminal region, however. The mRNA levels of PSP-S, trypsinogen, chymotrypsinogen, and colipase in CCP and control pancreas were compared. PSP-S mRNA was three times lower in CCP than in control, whereas the others were not altered. It was concluded that PSP-S gene expression is specifically reduced in CCP patients.

Topics: Adolescent; Adult; Amino Acid Sequence; Bacteriophage lambda; Base Sequence; Blotting, Northern; Calcium-Binding Proteins; Chronic Disease; Chymotrypsinogen; Colipases; DNA; Female; Gene Expression Regulation; Humans; Lithostathine; Male; Molecular Sequence Data; Nerve Tissue Proteins; Nucleic Acid Hybridization; Pancreatic Juice; Pancreatitis; RNA, Messenger; Sequence Homology, Nucleic Acid; Trypsinogen

In order to investigate the role of renal factors in affecting trypsinogen 1 metabolism and excretion in chronic pancreatic disease, serum immunoreactive trypsin (IRT), urinary IRT, gamma-glutamyltransferase (GGT), alpha-glucosidase (AGL) and RNase outputs and the molecular size distribution of serum and urine IRT were studied in 8 control subjects, 18 cases with pancreatic cancer, and 23 cases with chronic pancreatitis. Serum chromatography demonstrated that most immunoreactivity eluted as trypsinogen 1. Smaller amounts of immunoreactivity at higher molecular weights were also observed. Urine chromatography displayed both trypsinogen 1 and heavier molecular forms. An inverse linear correlation was noticed between creatinine clearance and serum trypsinogen 1 levels. Multiple regression analysis (urinary IRT output dependent and GGT, AGL, and RNase predictor variables) showed a significant linear correlation. RNase was found to be the most important parameter in explaining urinary IRT output. Mild variations in the glomerular function seem to be able to influence serum trypsinogen 1 levels. Urinary IRT excretion is principally explained by a disturbance in the tubular reabsorption of low molecular weight proteins, such as RNase.

Topics: Adult; Aged; Chronic Disease; Female; Humans; Kidney; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Trypsin; Trypsinogen

In order to investigate the role of circulating free trypsinogen and renal tubular dysfunction in affecting trypsin plasma-urine transfer, serum immunoreactive trypsin (IRT), its urinary output, IRT molecular size distribution, filtrable immunoreactive trypsin, gamma-glutamyltransferase and alpha-glucosidase outputs were studied in 6 control subjects, 9 patients with pancreatic cancer and 15 with chronic pancreatitis. The majority of immunoreactivity was always eluted at a molecular weight of about 24,000 and might therefore be considered as free trypsinogen. Variable amounts of IRT at higher molecular weights, possibly represented by trypsin-inhibitor complexes, were also detected. Increasing IRT levels were generally accounted for by free trypsinogen, regardless of the nature of the disease. Unlike serum free trypsinogen levels, renal tubular damage, evaluated by means of the excretion of two high-molecular weight urinary enzymes, seems to play a prominent role in explaining trypsin plasma-urine transfer.

Topics: Adolescent; Adult; Aged; alpha-Glucosidases; Carcinoma, Intraductal, Noninfiltrating; Chronic Disease; Female; gamma-Glutamyltransferase; Humans; Kidney Diseases; Kidney Tubules; Male; Metabolic Clearance Rate; Middle Aged; Molecular Weight; Pancreatic Neoplasms; Pancreatitis; Trypsin; Trypsinogen

Ultrasonic monitoring of the pancreas following secretin stimulation has shown to cause a marked dilatation of Wirsung duct; whether this phenomenon is due to the stimulation of pancreatic secretion and/or to the effect of secretin on the sphincter of Oddi (SO) motility is unknown. In the present study pancreatic scan after secretin was performed in 11 patients with nonpancreatic diseases after premedication with glucagon (inhibition of both pancreatic secretion and SO motility) or tyropramide (inhibition of SO motor function) and in patients with different degrees of pancreatic insufficiency. Serum immunoreactive trypsinogen (IRT) levels were measured in all the subjects during the test. Premedication with glucagon completely abolished both Wirsung enlargement and serum IRT increase, while tyropramide significantly reduced, but did not abolish, the response to secretin. These results suggest that both stimulation of pancreatic secretion and the increase of SO pressure are prerequisites for a full-blown occurrence of the secretin-induced modifications of Wirsung. Within chronic pancreatitis patients, the response to secretin was exaggerated in those with a still preserved pancreatic function and it was lacking in those with severe pancreatic insufficiency.

Topics: Chronic Disease; Common Bile Duct Diseases; Dilatation, Pathologic; Humans; Pancreas; Pancreatic Diseases; Pancreatic Ducts; Pancreatitis; Secretin; Sphincter of Oddi; Trypsinogen; Ultrasonography

We evaluated the behavior of serum cationic trypsinogen (SCT), an enzyme of solely pancreatic origin, in 30 patients with chronic pancreatitis and 25 healthy subjects as a control, after secretin and bombesin stimulation. After both the stimulations, serum cationic trypsinogen is unable to distinguish between the healthy control subjects and the patients with chronic pancreatitis. On the other hand, after secretin, the enzyme is able to separate chronic pancreatitis patients with different levels of exocrine function insufficiency. It does so with a greater statistical significance than that obtained by the rapid injection of bombesin and equal to that of trypsin into the duodenal juice during duodenal intubation. For these reasons, as well as the absence of any side-effects, secretin is preferred to bombesin stimulation in the evaluation of the exocrine pancreatic function in patients with chronic pancreatitis.

Topics: Adult; Alcoholism; Bombesin; Cations; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreatitis; Secretin; Trypsinogen

The levels of serum immunoreactive trypsinogen and P-isoamylase in response to Bombesin intravenous infusion were evaluated in 25 controls, 18 patients with documented chronic pancreatitis, and nine subjects with nonpancreatic gastroenterological diseases. Mean immunoreactive trypsinogen peak values were significantly higher in controls and gastroenterological diseases than in chronic pancreatitis, but there was marked overlap in individual values between the three groups. As for P-isoamylase, a statistical difference was detected only between mean peak concentrations of control versus chronic pancreatitis. Integrated responses for both enzymes did not result in a better discrimination between controls, chronic pancreatitis, and gastroenterological diseases. This study confirms that evocative tests are of limited value in the diagnosis of pancreatic disease.

Topics: Bombesin; Chronic Disease; Female; Glycoside Hydrolases; Humans; Isoamylase; Male; Pancreas; Pancreatic Function Tests; Pancreatitis; Trypsinogen

Previous studies, in selected populations, have determined that a low serum trypsinogen can be seen in chronic exocrine pancreatic disorders (CP) and primary diabetes mellitus (DM). In this study, we investigated the predictive value of a low serum trypsinogen. The study population consisted of 488 consecutive emergency room patients admitted to our hospital on whom a serum amylase was drawn by the emergency room staff. Of the sera drawn, 418 were saved and tested for immunoassayable trypsinogen. Ten of 418 (2.4%), had a low level of this marker (less than 10 ng/ml). Of these 10, four had obvious historical or clinical evidence of CP during their initial hospitalization. Six patients, however, had no initial evidence of CP. Follow-up was obtained in three of the six, and all three had evidence of CP despite absence of symptoms. Of the 418 patients, 37 had DM. A low trypsinogen was found in three of these 37, and all three had concomitant CP. We conclude that this new assay has excellent predictive value in diagnosing chronic exocrine pancreatic disorders.

Topics: Adult; Aged; Chronic Disease; Diabetes Mellitus; Emergency Service, Hospital; Female; Humans; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Trypsinogen

Topics: Chronic Disease; Clinical Enzyme Tests; Humans; Pancreatitis; Trypsinogen

A new radioimmunoassay to serum trypsinogen (Cis Trypsik) was tested in several patient populations. A low serum trypsinogen level (less than 10 ng/ml) was found in 69.2% of 13 patients with chronic pancreatic insufficiency (CPI), in 100% of 10 patients with 95-100% pancreatectomy but only in 14% of 14 patients with cancer of the pancreas. A low trypsinogen level was not found in any of 68 control subjects or 10 patients with nonpancreatic steatorrhea. Nine patients with CPI or 95% pancreatectomy were retested a mean of six months after initial testing. Four of these nine (44.4%) had a significant variation in serum trypsinogen which would have led to a different diagnostic interpretation (two went from low to normal levels and two from normal to low levels). A mixed meal had little effect on serum trypsinogen levels in five of six patients with CPI, and pancreatic enzyme replacement therapy had no consistent effect on the serum trypsinogen level in seven patients with CPI or 95% pancreatectomy. It is speculated that minor subclinical episodes of focal pancreatitis may effect the serum trypsinogen level. Although there can be considerable variability using this assay, it still offers important clinical utility. A low trypsinogen level points to a chronic pancreatic process with excellent specificity. A normal trypsinogen level is of no help and should be repeated if clinical suspicion of chronic pancreatitis remains high.

Topics: Chronic Disease; Female; Humans; Male; Pancreatitis; Trypsinogen

SDS electrophoresis on polyacrylamide gels of purified trypsinogen 1 has shown the occurrence of a proteolysis in some molecules during long storage at -20 degrees C. This proteolyzed trypsinogen gives a positive reaction with an antiserum directed against the precipitate protein, major protein of about 14 000 molecular weight extracted from precipitates present in the pancreatic juice of patients with chronic pancreatitis. The autoactivation of proteolyzed trypsinogen 1 liberates a polypeptide of 14 000 molecular weight which is immunologically identical to the precipitate protein. These results show that the major protein present in pancreatic precipitates (and pancreatic stones) of patients with chronic pancreatitis is a degradation product of trypsinogen 1 liberated by a proteolysis which necessarily requires a premature zymogen activation in the disease.

Topics: Chronic Disease; Electrophoresis, Polyacrylamide Gel; Humans; Immunoelectrophoresis; Isoenzymes; Molecular Weight; Pancreatic Juice; Pancreatitis; Trypsinogen

Topics: Chronic Disease; Humans; Pancreatic Juice; Pancreatitis; Trypsinogen

Serological tests used in pancreatic diseases, especially isoamylase analysis and trypsin radioimmunoassay are presented. The results show that these markers are helpful in the diagnosis of chronic pancreatic diseases.

Topics: Adolescent; Amylases; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Humans; Infant; Isoenzymes; Lipase; Pancreatic Diseases; Trypsinogen

Immunoreactive trypsin was localized with the peroxidase-antiperoxidase technique in normal human pancreatic tissue and in the glands of patients suffering from acute or chronic pancreatitis. In the normal pancreas and in the histologically normal areas of the inflamed pancreas, trypsin was detected in the zymogen granules of acinar cells and in ductal secretory material. During acute pancreatitis, three characteristic changes were observed: (1) separate acinar cell fragments in early lesions; (2) decreased and evenly dispersed staining in necrotic acinar cells, and (3) intensive reaction in plugs in acinar lumina in advanced lesions. In chronic pancreatitis, the localization of trypsin in acinar cells was similar to that in normal pancreas. Some proteinaceous plugs in dilated pancreatic ducts were weakly immunoreactive. The results show that the tissue distribution of immunoreactive trypsin is altered in acute pancreatitis.

Topics: Acute Disease; Adult; Aged; Chronic Disease; Cytoplasmic Granules; Enzyme Precursors; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Pancreas; Pancreatitis; Trypsin; Trypsinogen

Topics: Acute Disease; Adult; Animals; Cacodylic Acid; Callitrichinae; Cattle; Celiac Disease; Child; Chlorocebus aethiops; Chronic Disease; Dianisidine; Duodenum; Endopeptidases; Enteropeptidase; Guinea Pigs; Histocytochemistry; Humans; Intestine, Small; Mice; Mice, Inbred Strains; Oligopeptides; Pancreatitis; Rats; Swine; Swine, Miniature; Trypsinogen